Editors' ChoiceCancer therapy

A Complex Target

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Science's STKE  30 Sep 2003:
Vol. 2003, Issue 202, pp. tw379-TW379
DOI: 10.1126/stke.2003.202.tw379

Heat shock protein 90 (HSP90) functions as a molecular chaperone that regulates the conformation of many signaling proteins implicated in oncogenesis. Thus, HSP90 comprises an appealing therapeutic target that could be blocked to achieve concurrent inhibition of multiple signaling pathways. Preclinical data suggest that, although HSP90 is expressed at high levels in normal cells, the HSP90 inhibitor 17-allylaminogeldanamycin (17-AAG) selectively kills cancer cells. The reason for this selectivity, however, has been unclear (see Neckers and Lee). Kamal et al. used a competitive binding assay to show that 17-AAG had a higher binding affinity for HSP90 from malignant cell lysates than HSP90 from normal cell lysates or purified HSP90. The authors used immunoprecipitation together with Western analysis to show that, although normal and malignant cells contained comparable levels of HSP90, HSP90 from tumor cells--but not normal cells--was almost entirely in multiprotein complexes with cochaperones. HSP90 from tumor cells showed higher adenosine 5´-triphosphatase (ATPase) activity than that from normal cells, indicating that tumor HSP90 was functionally active. When purified HSP90 was reconstituted in vitro with four cochaperones (HSP70, HSP40, Hop, and p23), both its affinity for 17-AAG and its ATPase activity increased. The authors proposed a model in which HSP90 facilitates malignant progression by rescuing mutant and overexpressed proteins and thereby enabling cell survival. The context-dependent affinity of HSP90 for at least some inhibitors--together with its regulation of various oncoproteins--may allow it to serve as a valuable target in cancer therapy.

A. Kamal, L. Thao, J. Sensintaffar, L. Zhang, M. F. Brown, L. C. Fritz, F. J. Burrows, A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407-410 (2003). [Online Journal]

L. Neckers, Y.-S. Lee, The rules of attraction. Nature 425, 357-358 (2003). [Online Journal]

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